Cis-substituted fluoromethylpyrrolidine derivative

ABSTRACT

An antibacterial drug having potent antibacterial activities upon various bacteria including resistant strains and high safety is disclosed, which comprises as an active ingredient, quinolone derivatives represented by the following formula (I), its salts or hydrates thereof:  
                 
 
     wherein R 1  represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,  
     R 2  represents a halogenomethoxyl group or an alkoxyl group,  
     R 3  represents an alkyl group, an alkenyl group, a halogenoalkyl group, a cyclic alkyl group, a heteroaryl group, an alkoxyl group or an alkylamino group, and  
     R 4  represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, 3-acetoxy-2-oxobutyl group, an alkyl group, an alkoxylmethyl group or a phenylalkyl group. These substituents may further have additional substituents.

TECHNICAL FIELD

[0001] This invention relates to an8-(substituted)alkoxy-4-oxoquinoline-3-carboxylic acid derivative having3-(S)-amino-4-(S)-fluoromethylpyrrolidin-1-yl group at the 7-position ofthe quinoline nucleus as a substituent, which has excellentantibacterial activity, good pharmacokinetics and high safety, and to anantibacterial agent and an antibacterial preparation, which contain thecompound.

[0002] This invention also relates to a compound which is useful forintroducing a substituent at the 7-position that has such a structurethat excellent antibacterial activity, pharmacokinetics and safety canbe added to synthetic quinolone antibacterial agents in which thestructure of the substituent at the 7-position exerts importantinfluences upon the antibacterial activity, pharmacokinetics and safety.

BACKGROUND ART

[0003] Since the discovery of norfloxacin, antibacterial activity andpharmacokinetics of quinolone synthetic antibacterial agents have beenimproved, and many compounds are now used in the clinical field aschemotherapeutic agents which are effective in almost systemicinfectious diseases.

[0004] In recent years, generation of bacteria having low sensitivity toquinolone synthetic antibacterial agents has been increasing in thefield of clinics. For example, like the case of Staphylococcus aureus(MRSA) which is non-sensitive to β-lactam antibiotics, a case has beenincreasing in which a bacterium originally resistant to drugs other thanquinolone synthetic antibacterial agents becomes low-sensitive toquinolone synthetic antibacterial agents too. In consequence,development of a drug having further high efficacy has been called forin the field of clinics. On the other hand, it has been revealed thatquinolone synthetic antibacterial agents cause a side effect in whichsevere convulsion is induced when a non-steroidal anti-inflammatory drugis simultaneously used, as well as other side effects such asphototoxicity and the like, so that development of a quinolone syntheticantibacterial agent having higher safety has also been called for in thefield.

[0005] Quinolone-carboxylic acid derivatives which has thecis-3-amino-4-fluoromethylpyrrolidin-1-yl group related to the presentinvention as a substituent are disclosed for example in JP-A-62-19583,JP-A-63-45261 and JP-A-63-152318 (the term “JP-A” as used herein meansan “unexamined published Japanese patent application”), and thesepatents describe compounds represented by the following formula.However, though the substituent at the 7-position of these disclosedquinolones is a cis-3-amino-4-fluoromethylpyrrolidin-1-yl group, theyare compounds which have the 8-fluoroquinoline nucleus in which the8-position substituent is a halogen atom, and nothing is described abouta compound which has the 8-methoxyquinoline nucleus related to thepresent invention. In addition, there is no illustrative disclosure inthese specifications concerning an optically active compound3-(S)-amino-4-(S)-fluoromethylpyrrolidine or3-(S)-amino-4-(S)-fluoromethylpyrrolidinyl group.

[0006] (In the above formula, R⁵ is a hydrogen atom or a fluorine atom.Definition of the substituent of the compound represented by the formula(III) is unrelated to the compound of the present invention.)

[0007] In addition, JP-A-3-188074 discloses a compound represented bythe following formula (IV), but it does not disclose a compound whichhas the 1-cyclopropyl-8-methoxyquinoline nucleus related to the presentinvention. Also, there is no illustrative disclosure in thespecification concerning an optically active compound3-(S)-amino-4-(S)-fluoromethylpyrrolidine or3-(S)-amino-4-(S)-fluoromethylpyrrolidinyl group.

[0008] (In the above formula, R⁶ is a hydrogen atom or an amino group.Definition of the substituent of the compound represented by the formula(IV) is unrelated to the compound of the present invention.)

[0009] Also, JP-A-4-211077 discloses a compound which has the1-cyclopropyl-8-methoxyquinoline nucleus, represented by the followingformula (V). However, there is no illustration in the specificationconcerning a compound substituted with3-(S)-amino-4-(S)-fluoromethylpyrrolidinyl group.

[0010] (In the above formula, R⁷ is methyl, ethyl or the like loweralkyl group. Definition of the substituent of the compound representedby the formula (V) is unrelated to the compound of the presentinvention.)

[0011] In addition, there is no description in the just describedspecification about safety of a compound represented by the followingformula (VI) in which R⁷ is a methyl group.

DISCLOSURE OF INVENTION

[0012] The inventors of the present invention have carried out tests onthe safety of the compound represented by the formula (VI) and found asthe result that its mouse peripheral blood micronucleus test waspositive (micronucleus inducing action).

[0013] The present inventors have conducted intensive studies with theaim of providing a compound which has excellent antibacterial activity,high efficacy and excellent safety in the clinical field. As the result,it has been found that an 8-methoxyquinoline compound substituted with3-(S)-amino-4-(S)-fluoromethylpyrrolidin-1-yl group, represented by thefollowing formula (I), is superior to its corresponding8-methoxyquinoline compound substituted with3-(S)-amino-4-(S)-methylpyrrolidin-1-yl group, represented by theaforementioned formula (VI), thereby resulting in the accomplishment ofthe present invention.

[0014] That is, it has been found that the compound represented by thefollowing formula (I) is possessed of excellent antibacterial activityupon a broad range of Gram-negative and Gram-positive bacteria and haveexcellent safety and pharmacokinetics, such as its micronucleustest-negative property.

[0015] [In the above formula, R¹ represents a hydrogen atom or an alkylgroup having 1 to 6 carbon atoms, wherein the alkyl group may have oneor more substituent(s) selected from the group consisting of a hydroxylgroup, a halogen atom, an alkylthio group having 1 to 6 carbon atoms andan alkoxyl group having 1 to 6 carbon atoms,

[0016] R² represents a halogenomethoxyl group or an alkoxyl group having1 to 6 carbon atoms,

[0017] R³ represents an alkyl group having 1 to 6 carbon atoms, analkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms whichmay have a substituent, a heteroaryl group which may have a substituent,an alkoxyl group having 1 to 6 carbon atoms or an alkylamino grouphaving 1 to 6 carbon atoms, and

[0018] R⁴ represents a hydrogen atom, a phenyl group, an acetoxymethylgroup, a pivaloyloxymethyl group, an ethoxycarbonyl group, a cholinegroup, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinylgroup, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, 3-acetoxy-2-oxobutylgroup, an alkyl group having 1 to 6 carbon atoms, an alkoxylmethyl grouphaving 2 to 7 carbon atoms or a phenylalkyl group composed of analkylene group having 1 to 6 carbon atoms and a phenyl group.

[0019] In this connection, the substituent R⁴ may also be aboron-containing group represented by the following formula:

−B(Y¹¹)Y¹²

[0020] wherein Y¹¹ and Y¹², each independently represents a fluorineatom or an alkylcarbonyloxy group having 2 to 4 carbon atoms.]

[0021] Accordingly, the present invention relates to a compoundrepresented by the aforementioned formula (I), its salts or hydratesthereof.

[0022] The present invention also relates to the aforementioned8-methoxyquinolone-carboxylic acid derivative, its salts or hydratesthereof in which the compound of formula (I) is a stereochemically purecompound; the aforementioned compound, its salts or hydrates thereof,wherein R¹ in the formula (I) is a hydrogen atom; the aforementionedcompound, its salts or hydrates thereof, wherein R² in the formula (I)is a methoxyl group;7-[3-(S)-amino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof, wherein R³ in the formula (I) is acyclopropyl group; the aforementioned compound, its salts or hydratesthereof, wherein R³ in the formula (I) is a halogenocyclopropyl group;the aforementioned compound, its salts or hydrates thereof, wherein R³in the formula (I) is a 1,2-cis-halogenocyclopropyl group; theaforementioned compound, its salts or hydrates thereof, wherein R³ inthe formula (I) is a stereochemically pure substituent; theaforementioned compound, its salts or hydrates thereof, wherein R³ inthe formula (I) is a (1R,2S)-2-halogenocyclopropyl group;7-[3-(S)-amino-4-(S)-fluoromethyl-1-pyrrolidinyl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof, wherein R³ in the formula (I) is a(1R,2S)-2-fluorocyclopropyl group; a medicament which comprises theaforementioned compound, a hydrate thereof, a salt of the compound or ahydrate of the salt as an active ingredient; and an antibacterial agentor antibacterial preparation which comprises the aforementionedcompound, a hydrate thereof, a salt of the compound or a hydrate of thesalt as an active ingredient.

[0023] The present invention also relates to a compound represented bythe following formula (II), its salts or hydrates thereof:

[0024] (wherein R¹¹ and R¹² each independently represents a hydrogenatom, an alkyl group having 1 to 6 carbon atoms or a protective group ofthe amino group,

[0025] wherein the alkyl group may have one or more substituent(s)selected from the group consisting of a hydroxyl group, a halogen atom,an alkylthio group having 1 to 6 carbon atoms and an alkoxyl grouphaving 1 to 6 carbon atoms, and

[0026] Q′ represents a protective group of the amino group or a hydrogenatom); and also relates to the aforementioned compound, its salts orhydrates thereof, wherein the protective group of the amino group is aprotective group selected from the group consisting of (substituted)alkoxycarbonyl groups, (substituted) aralkyloxycarbonyl groups,(substituted) acyl groups, (substituted) alkyl groups, (substituted)aralkyl groups and (substituted) silyl groups;

[0027] the aforementioned compound, its salts or hydrates thereof,wherein the protective group of the amino group is a protective groupselected from the group consisting of a tert-butoxycarbonyl group, a2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, apara-methoxybenzyloxycarbonyl group, a para-nitrobenzyloxycarbonylgroup, an acetyl group, a methoxyacetyl group, a trifluoroacetyl group,a chloroacetyl group, a pivaloyl group, a formyl group, a benzoyl group,a tert-butyl group, a benzyl group, a para-nitrobenzyl group, apara-methoxybenzyl group, a (R)-1-phenylethyl group, a (S)-1-phenylethylgroup, a triphenylmethyl group, a methoxymethyl group, atert-butoxymethyl group, a tetrahydropyranyl group, a2,2,2-trichloroethoxymethyl group, a trimethylsilyl group, anisopropyldimethylsilyl group, a tert-butyldimethylsilyl group, atribenzylsilyl group and a tert-butyldiphenylsilyl group;

[0028] the aforementioned compound, its salts or hydrates thereof,wherein one of R¹¹ and R¹² and Q′ are protective groups of the aminogroup, which are different from each other;3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethyl-1-(R)-phenylethylpyrrolidine,its salts or hydrates thereof;3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethylpyrrolidine, its saltsor hydrates thereof; and

[0029] the aforementioned compound, its salts or hydrates thereof,wherein one of R¹¹ and R¹² and Q′ are protective groups of the aminogroup, which are severed under different reaction conditions.

MODE FOR CARRYING OUT INVENTION

[0030] Each of the substituents of the compound of the present inventionrepresented by formula (I):

[0031] (wherein R¹, R², R³ and R⁴ are as defined in the foregoing) isdescribed in the following.

[0032] The substituent R¹ is a hydrogen atom or an alkyl group having 1to 6 carbon atoms, wherein the alkyl group may have one or moresubstituent(s) selected from the group consisting of a hydroxyl group, ahalogen atom, an alkylthio group having 1 to 6 carbon atoms and analkoxyl group having 1 to 6 carbon atoms.

[0033] The alkyl group may be any straight or branched group having 1 to6 carbon atoms, and its preferred examples include a methyl group, anethyl group, a normal propyl group and an isopropyl group.

[0034] When the alkyl group has a hydroxyl group as a substituent, thealkyl group may be either straight or branched form having 1 to 6 carbonatoms, and the substituting position of hydroxyl group may preferably beon the terminal carbon atom of the alkyl group. Preferred examples ofthe alkyl group having a hydroxyl group include those which have up to 3carbon atoms, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl,3-hydroxypropyl and the like groups.

[0035] When the alkyl group has a halogen atom as a substituent, thealkyl group may be either straight or branched form having 1 to 6 carbonatoms, and a fluorine atom is desirable as the halogen atom.

[0036] When the alkyl group has an alkylthio group as a substituent, thealkyl group may be either straight or branched form having 1 to 6 carbonatoms, and the alkylthio group may also be either straight or branchedform having 1 to 6 carbon atoms. An alkylthiomethyl group, analkylthioethyl group or an alkylthiopropyl group is desirable as thealkyl group having an alkylthio group, and the alkylthio group maypreferably have up to 3 carbon atoms. Its more preferred examplesinclude a methylthiomethyl group, an ethylthiomethyl group and amethylthioethyl group.

[0037] When the alkyl group has an alkoxyl group as a substituent, thealkyl group may be either straight or branched form having 1 to 6 carbonatoms, and the alkoxyl group may also be either straight or branchedform having 1 to 6 carbon atoms. An alkoxymethyl group, an alkoxyethylgroup or an alkoxypropyl group is desirable as the alkyl group having analkoxyl group, and the alkoxyl group may preferably have up to 3 carbonatoms. Its more preferred examples include a methoxymethyl group, anethoxymethyl group and a methoxyethyl group.

[0038] The substituent R² is a halogenomethoxyl group or an alkoxylgroup having 1 to 6 carbon atoms.

[0039] As the halogen of the halogenomethoxyl group, a fluorine atom isparticularly desirable, and its number may be from 1 to 3.

[0040] The alkoxyl group may be an alkoxyl group having 1 to 6 carbonatoms, preferably a methoxyl group and an ethoxyl group.

[0041] Among these substituents, a difluoromethoxyl group and a methoxylgroup are preferred, and a methoxyl group is more preferred.

[0042] The substituent R³ is an alkyl group having 1 to 6 carbon atoms,an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl grouphaving 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbonatoms which may have a substituent, a heteroaryl group which may have asubstituent, an alkoxyl group having 1 to 6 carbon atoms, an alkylaminogroup having 1 to 6 carbon atoms or an aryl group which may have one ormore substituent(s).

[0043] In this case, an ethyl group is desirable as the alkyl grouphaving 1 to 6 carbon atoms. A vinyl or 1-isopropenyl group is desirableas the alkenyl group having 2 to 6 carbon atoms. A 2-fluoroethyl groupis desirable as the halogenoalkyl group having 1 to 6 carbon atoms. Acyclopropyl or 2-halogenocyclopropyl group is desirable as the cyclicalkyl group having 3 to 6 carbon atoms which may have a substituent, anda fluorine atom is particularly desirable as the halogen atom of the2-halogenocyclopropyl group.

[0044] Examples of the aryl group which may have one or moresubstituent(s) include phenyl or the like group which may have 1 to 3substituents selected from the group consisting for example of fluorine,chlorine, bromine or the like halogen atom, a lower alkyl group having 1to 6 carbon atoms, a hydroxyl group, an amino group, a nitro group and alower alkoxyl group having 1 to 6 carbon atoms, and its preferredillustrative examples include a phenyl group, a 2-fluorophenyl group, a4-fluorophenyl group, a 2,4-difluorophenyl group and a2-fluoro-4-hydroxyphenyl group.

[0045] The heteroaryl group is a group derived from an aromaticheterocyclic compound which contains one or more hetero-atoms selectedfrom a nitrogen atom, an oxygen atom and a sulfur atom. Its examplesinclude pyridyl, pyrimidyl and the like groups. As a substituent onthese rings, an alkyl group, a halogen atom or the like is desirable. Amethoxyl group is desirable as the alkoxyl group having 1 to 6 carbonatoms. A methylamino group is desirable as the alkylamino group having 1to 6 carbon atoms.

[0046] As the substituent R³, a cyclic alkyl group or ahalogenocycloalkyl group is desirable. Among these groups, a cyclopropylgroup or a 2-halogenocyclopropyl group is particularly desirable. Afluorine atom is desirable as the halogen atom.

[0047] Next, the halogenocyclopropyl group of R³ is described.

[0048] As the substituting halogen atom, fluorine and chlorine can beexemplified, and fluorine is particularly preferred.

[0049] Stereochemical environment at this moiety with respect to thecyclopropane ring, it is particularly desirable that the halogen atomand the pyridonecarboxylic acid moiety are located in thecis-configuration.

[0050] So-called enantiomeric isomers exist solely by thecis-2-halogenocyclopropyl moiety of R³, and strong antibacterialactivity and high safety have been observed in all of these isomers.

[0051] The present invention exerts excellent characteristics as thesubstituent represented by formula (VII):

[0052] is substituted at the 7-position of the6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid nucleus.

[0053] The present invention is characterized in that the amino group atthe 3-position and the fluoromethyl group at the 4-position on thepyrrolidine ring of this substituent are located in thecis-configuration and absolute configuration of (3S,4S)-form.

[0054] That is, it has been found that, when the substituent at the7-position of the 6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acidnucleus is 3-(S)-amino-4-(S)-fluoromethylpyrrolidin-1-yl group, thecompound of the present invention shows potent antibacterial activityupon Gram-negative and Gram-positive bacteria and also shows excellentsafety and good pharmacokinetics, such as negative property inmicronucleus test, markedly weak theophylline metabolism inhibitoryactivity and the like.

[0055] When the compound of the formula (I) of the present invention hasa structure in which diastereomers are present, and when such a compoundof the present invention is administered to human and animals, it isdesirable to administer a compound which comprises a singlediastereomer. The term “single” of “comprises a single diastereomer” asused herein means not only a case in which it is completely free fromthe other diastereomer but also a case in which it is in a chemicallypure degree. In other words, it is interpretable that the otherdiastereomer may be present in such a degree that it does not exertinfluences upon physical constants and physiological activities of thecompound.

[0056] Also, the term “stereochemically pure” as used herein means that,when a compound or the like exists in a plurality of isomer forms due tothe presence of asymmetric carbon atoms, the compound is comprised ofonly one of them. The term “pure” in this case can also be considered inthe same manner as the term “single” described above.

[0057] The 6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acidderivative of the present invention may be used either in its free formor as an acid addition salt or a salt of its carboxyl group. Examples ofthe acid addition salt include hydrochloride, sulfate, nitrate,hydrobromide, hydroiodide, phosphate and the like inorganic acid salts,or acetate, methanesulfonate, benzenesulfonate, toluenesulfonate,citrate, maleate, fumarate, lactate and the like organic acid salts.

[0058] The salt of carboxyl group may be either inorganic or organicsalt, and its illustrative examples include lithium salt, sodium salt,potassium salt and the like alkali metal salts, magnesium salt, calciumsalt and the like alkaline earth metal salts, ammonium salt, ortriethylamine salt, N-methylglucamine salt,tris-(hydroxylmethyl)aminomethane salt and the like.

[0059] Also, these free form, acid addition salts and salts of carboxylgroup of the 6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acidderivative may be present as hydrates.

[0060] On the other hand, a quinolone derivative whose carboxylic acidmoiety is an ester is useful as a synthesis intermediate or a prodrug.For example, alkyl esters, benzyl esters, alkoxyalkyl esters,phenylalkyl esters and phenyl esters are useful as synthesisintermediates.

[0061] Also, the ester to be used as a prodrug is an ester which iseasily cleaved after administered to form free carboxylic acid, and itsillustrative examples include acetoxymethyl ester, pivaloyloxymethylester, ethoxycarbonyl ester, choline ester, dimethylaminoethyl ester,5-indanyl ester, phthalidinyl ester, and5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl ester, 3-acetoxy-2-oxobutyl eater orthe like oxoalkyl ester.

[0062] The compound of the present invention represented by the formula(I) can be produced by various method, and, in an preferred example ofthese methods, it can be produced for example by allowing a compoundrepresented by formula (VIII):

[0063] [wherein X¹ is a substituent which serves as a leaving group,such as a fluorine atom, a chlorine atom, substituted or unsubstitutedphenylsulfonyl group or a substituted or unsubstituted alkylsulfonylgroup having 1 to 3 carbon atoms, Y¹ is the R⁴ defined in the formula(I) or a boron-containing group represented by the following formula:

−B(Y¹¹)Y¹²

[0064] (wherein each of Y¹¹ and Y¹² is a fluorine atom or analkylcarbonyloxy group having 2 to 4 carbon atoms), and R² and R³ are asdefined in the formula (I)] to react with a compound represented byformula (IX):

[0065] (wherein R¹¹ and R¹², each independently represents a hydrogenatom, an alkyl group having 1 to 6 carbon atoms or a protective group ofthe amino group,

[0066] wherein the alkyl group may have one or more substitutent(s)selected from the group consisting of a hydroxyl group, a halogen atom,an alkylthio group having 1 to 6 carbon atoms and an alkoxyl grouphaving 1 to 6 carbon atoms, or an addition salt thereof (as the acidaddition salt, an inorganic acid salt or an organic acid salt can beexemplified, and its illustrative examples include hydrochloride,sulfate, nitrate, hydrobromide, hydroiodide, phosphate and the likeinorganic acid salts, or methanesulfonate, benzenesulfonate,toluenesulfonate (sulfonates), acetate, citrate, maleate, fumarate,lactate (carboxylates) and the like organic acid salts).

[0067] The reaction can be carried out using or without using a solvent.The solvent to be used in the reaction may be any solvent which is inertunder the reaction conditions, and its illustrative examples includedimethyl sulfoxide, pyridine, acetonitrile, ethanol, chloroform,dimethylformamide, dimethylacetamide, N-methylpyrrolidone,tetrahydrofuran, water, 3-methoxybutanol and the like or a mixturethereof.

[0068] Preferably, the reaction may be carried out in the presence of anacid acceptor such as an inorganic base or an organic base, whichincludes an alkali metal or alkaline earth metal carbonate orbicarbonate or the like inorganic basic compound, or triethylamine,pyridine, 1,8-diazabicycloundecene or the like organic basic compound.

[0069] The reaction temperature may be within the range of generallyfrom room temperature to 200° C., preferably from approximately 25 to150° C. The reaction is carried out for a period of from 30 minutes to48 hours and completes generally after about 30 minutes to 20 hours.

[0070] Examples of the protective group of the amino group to be used inthe compound represented by the formula (IX) include those which aregenerally used in this field, such as tert-butoxycarbonyl,2,2,2-trichloroethoxycarbonyl and the like (substituted) alkoxycarbonylgroups, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl,para-nitrobenzyloxycarbonyl and the like (substituted)aralkyloxycarbonyl groups, acetyl, methoxyacetyl, trifluoroacetyl,chloroacetyl, pivaloyl, formyl, benzoyl and the like (substituted) acylgroups, tert-butyl, benzyl, para-nitrobenzyl, para-methoxybenzyl,triphenylmethyl and the like (substituted) alkyl groups or (substituted)aralkyl groups, methoxymethyl, tert-butoxymethyl, tetrahydropyranyl,2,2,2-trichloroethoxymethyl and the like ethers and trimethylsilyl,isopropyldimethylsilyl, tert-butyldimethylsilyl, tribenzylsilyl,tert-butyldiphenylsilyl and the like substituted silyl groups (the term“(substituted)” as used herein means “which may have a substituent”).

[0071] When Y¹ is an alkyl group having 1 to 6 carbon atoms, analkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl groupcomposed of an alkylene group having 1 to 6 carbon atoms and a phenylgroup, the compound of interest can be converted into its correspondingcarboxylic acid by treating it under an acidic or basic condition whichis generally employed for the hydrolysis of carboxylic acid esters.

[0072] When Y¹ is a boron-containing group of the formula:

−B(Y¹¹)Y¹²,

[0073] its conversion into corresponding carboxylic acid can be effectedby allowing a compound represented by the formula (IX) to react with acompound of the formula (VIII) and then treating it under an acidic orbasic condition.

[0074] In addition, when deprotection is necessary, the compound ofinterest represented by the formula (I) can be obtained by removing theprotective group by selecting suitable conditions for the protectivegroup.

[0075] The compound represented by the formula (VIII) can be produced byalready known methods. Also, a compound in which Y¹ is aboron-containing group can be obtained by allowing the carboxylic acidor a ester derivative thereof to react with a boron fluoride compound oranhydrous boron carboxylate.

[0076] In the compound in which Y¹ is a boron-containing group, each ofY¹¹ and Y¹² is a fluorine atom or an acyloxy group. The acyloxy groupmay be either aliphatic (becomes an alkylcarbonyloxy group) or aromatic,and either may have an additional substituent. As such a substituent, itmay have one or more substituent(s) selected from the group consistingof a halogen atom, an alkyl group having 1 to 6 carbon atoms and analkoxyl group having 1 to 6 carbon atoms. Examples of the acyloxy groupinclude acetyloxy, propanoyloxy, butanoyloxy, benzoyloxy,phenylacetyloxy and the like groups, of which an acyloxy group having 2to 4 carbon atoms (an alkylcarbonyloxy group) is preferred and anacetyloxy group is particularly preferred.

[0077] The compound represented by the formula (IX) can be formed byremoving Q′ from the compound of formula (II):

[0078] [wherein R¹¹ and R¹², each independently represents a hydrogenatom, an alkyl group having 1 to 6 carbon atoms or a protective group ofthe amino group, wherein the alkyl group may have one or moresubstituent(s) selected from the group consisting of a hydroxyl group, ahalogen atom, an alkylthio group having 1 to 6 carbon atoms and analkoxyl group having 1 to 6 carbon atoms, and

[0079] Q′ represents a protective group of the amino group or a hydrogenatom, and

[0080] wherein the amino protective group may be a protective groupselected from the group consisting of (substituted) alkoxycarbonylgroups, (substituted) aralkyloxycarbonyl groups, (substituted) acylgroups, (substituted) alkyl groups, (substituted) aralkyl groups andsubstituted silyl groups.]

[0081] The compound represented by the formula (IX) and the compoundrepresented by the formula (II) can be produced by various method. Forexample, 3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethylpyrrolidinecan be synthesized in accordance with the method described as adesirable method in Reference Examples, though not particularly limited.

[0082] The compound represented by the formula (II) can also exist inthe form of a salt thereof, a hydrate thereof or a hydrate of the salt.Examples of its acid addition salt include an inorganic acid salt or anorganic acid salt, and its illustrative examples include hydrochloride,sulfate, nitrate, hydrobromide, hydroiodide, phosphate and the likeinorganic acid salts, or methanesulfonate, benzenesulfonate,toluenesulfonate (sulfonates), acetate, citrate, maleate, fumarate,lactate (carboxylates) and the like organic acid salts.

[0083] When one of R¹¹ and R¹² is a protective group of the amino groupand Q′ is also a protective group of the amino group, these groups maybe the same or different from each other, but it is convenient to obtaina compound in which each of them is removed under different reactioncondition, namely one of them is selectively removed but the otherremains un-removed, for the production the compound (I).

[0084] The following can be exemplified as R¹¹ or R¹² (either one ofthem) and Q′ which are the protective groups of the amino group. Thatis, they are (substituted) alkoxycarbonyl groups, (substituted)aralkyloxycarbonyl groups, (substituted) acyl groups, (substituted)alkyl groups, (substituted) aralkyl groups and substituted silyl groups.

[0085] Their illustrative examples include tert-butoxycarbonyl,2,2,2-trichloroethoxycarbonyl and the like (substituted) alkoxycarbonylgroups, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl,para-nitrobenzyloxycarbonyl and the like aralkyloxycarbonyl groups,acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl,benzoyl and the like (substituted) acyl groups, tert-butyl, benzyl,para-nitrobenzyl, para-methoxybenzyl, triphenylmethyl and the like(substituted) alkyl groups or (substituted) aralkyl groups,methoxymethyl, tert-butoxymethyl, tetrahydropyranyl,2,2,2-trichloroethoxymethyl and the like ethers and trimethylsilyl,isopropyldimethylsilyl, tert-butyldimethylsilyl, tribenzylsilyl,tert-butyldiphenylsilyl and the like substituted silyl groups.

[0086] Cis-2-fluorocyclopropylamine comprised of a single isomer whichis desirable for the synthesis of the compound of the formula (I)comprised of a single isomer can, for example, be synthesized by themethod described in JP-A-2-231475. Synthesis of the compound of theformula (I) comprised of a single isomer can, for example, be carriedout in accordance with the method described in JP-A-2-231475, using thethus obtained optically active cis-2-fluorocyclopropylamine derivativeas the material.

[0087] Since the compound of the present invention has potentantibacterial activities, it can be used as medicaments for use in humanbodies, animals and fishes or as preservatives of agricultural chemicalsand food.

[0088] When the compound of the present invention is used as amedicament for human bodies, its dosage may be within the range ofgenerally from 50 mg to 1 g, preferably from 100 mg to 300 mg, per dayper adult.

[0089] Its dosage as a drug for animals varies depending on the purposeof its administration (treatment or prevention), kind and size of eachanimal to be treated and kind and degree of each infected pathogenicbacterium, but the dosage may be within the range of generally from 1 mgto 200 mg, preferably from 5 mg to 100 mg, per 1 kg body weight per day.

[0090] The daily dose may be used once a day or by dividing it into 2 to4 doses per day. As occasion demands, the daily dose may exceed theaforementioned range.

[0091] Since the compound of the present invention has activity againsta broad range of microorganisms which cause various infectious diseases,it can treat, prevent or alleviate diseases induced by these pathogens.

[0092] Illustrative examples of bacteria or bacterioid microorganisms onwhich the compound of the present invention is effective include thosewhich belong to the genus Staphylococcus, Streptococcus pyogens,hemolytic streptococcus, enterococcus, pneumococcus, those which belongto the genus Peptostreptococcus, Neisseria gonorrhoeae, Escherichiacoli, those which belong to the genus Citrobacter, those which belong tothe genus Shigella, Klebsiella pneumoniae, those which belong to thegenus Enterobacter, those which belong to the genus Serratia, thosewhich belong to the genus Proteus, Pseudomonas aeruginosa, Haemophilusinfluenzae, those which belong to the genus Acinetobacter, those whichbelong to the genus Campylobacter, Chlamydia trachomatis and the like.

[0093] Illustrative examples of diseases which are induced by thesepathogens include folliculitis, furuncle, carbuncle, erysipelas,phlegmon, lymphangitis, felon, subcutaneous abscess, hidradenitis, acneconglobata, infectious atheroma, perirectal abscess, mastitis,superficial secondary infections after injury, burn injury, operativewound and the like, pharyngitis, acute bronchitis, tonsilitis, chronicbronchitis, bronchiectasis, diffuse bronchiolitis, secondary infectionof chronic respiratory disease, pneumonia, pyelonephritis, cystitis,prostatitis, epididymitis, gonococcal urethritis, nonspecificurethritis, cholecystitis, cholangitis, bacillary dysentery, enteritis,uterine adnexitis, intrauterine infection, bartholinitis, blepharitis,hordeolum, dacryocystitis, tarsadenitis, corneal ulcer, octitis media,sinusitis, periodentitis, pericoronitis, jaw infection, peritonitis,endocarditis, sepsis, meningitis, skin infection and the like.

[0094] The compound of the present invention is also effective againstvarious microorganisms which cause infectious diseases in animals, suchas those which belong to the genera Escherichia, Salmonella,Pasteurella, Haemophilus, Bordetella, Staphylococcus, Mycoplasma and thelike.

[0095] Illustrative examples of such diseases include colibacillosis,pullorum disease, avian paratyphoid, avian cholera, infectious coryza,staphylococcosis, mycoplasma infection and the like in the case ofbirds; colibacillosis, salmonellosis, pasteurellosis, haemophilusinfection, atrophic rhinitis, exudative epidermis, mycoplasma infectionand the like in the case of pigs; colibacillosis, salmonellosis,hemorrhagic sepsis, mycoplasma infection, bovine pleuropneumonia, bovinemastitis and the like in the case of cattle; colisepsis, salmonellainfection, hemorrhagic sepsis, uterine empyema, cystitis and the like inthe case of dogs; and exudative pleurisy, cystitis, chronic rhinitis,haemophilus infection, kitten diarrhea, mycoplasma infection and thelike in the case of cats.

[0096] The antibacterial preparation which comprises the compound of thepresent invention can be prepared by selecting appropriate preparationdepending on each administration method and employing generally usedvarious preparation method. With regard to the dosage forms of theantibacterial preparation which uses the compound of the presentinvention as its principal agent, tablets, powders, granules, capsules,solutions, syrups, elixirs, oily or aqueous suspensions and the like canbe exemplified as oral preparations.

[0097] With regard to injections, a stabilizing agent, an antisepticagent, a solubilizing agent and the like may be used in the preparation,and a solution which may contain these auxiliary agents may be containedin a container and made into a solid preparation by freeze-drying or thelike means to be re-dissolved when used. In addition, a single dose maybe contained in a single container or multiple doses may be contained inthe same container.

[0098] Also, solutions, suspensions, emulsions, ointments, gels, creams,lotions, sprays and the like can be exemplified as preparations forexternal use.

[0099] Solid preparations may contain pharmaceutically acceptableadditives together with the active compound and can be prepared forexample by mixing the compound with additives optionally selected fromfillers, extenders, binders, disintegrators, solubilization enhancingagents, moistening agents, lubricating agents and the like.

[0100] As liquid preparations, solutions, suspensions, emulsions and thelike can be exemplified, which may contain a suspending agent, anemulsifying agent and the like as additives.

[0101] Examples of the method for administering the compound of thepresent invention to animals include a method in which it is orallyadministered directly or by mixing it with feed, a method in which it ismade into a solution and then orally administered directly or by mixingit with drinking water or feed and a method in which it is administeredby injection.

[0102] With regard to the pharmaceutical preparations for use in theadministration of the compound of the present invention to animals, itcan be made optionally into powders, fine subtilaes, soluble powders,syrups, solutions or injections making use of the techniques generallyused in this field.

[0103] Formulation examples of the pharmaceutical preparations are shownbelow. TABLE 1 Formulation Example 1 (Capsules): Compound of InventiveExample 2 100.0 mg Corn starch 23.0 mg CMC calcium 22.5 mg Hydroxymethylcellulose 3.0 mg Magnesium stearate 1.5 mg Total 150.0 mg FormulationExample 2 (Solutions): Compound of Inventive Example 2 1-10 g Aceticacid or sodium hydroxide 0.5-2 g Ethyl para-hydroxybenzoate 0.1 gPurified water 87.9-98.4 g Total 100 g Formulation Example 3 (Powdersfor feed mixing use): Compound of Inventive Example 2 1-10 g Corn starch98.5-89.5 g Light anhydrous silicic acid 0.5 g Total 100 g

BEST MODE FOR CARRYING OUT INVENTION

[0104] Examples of the present invention are given below by way ofillustration and not by way of limitation. The antibacterial activity ofeach compound of interest was measured in accordance with the standardmethod specified by the Japan Society of Chemotherapy, with the resultsshown in Table 1 as MIC values (μg/ml).

REFERENCE EXAMPLE 1

[0105] 4-(S)-Fluoromethyl-N-[1-(R)-phenylethyl]-2-pyrrolidone

[0106] Method A:

[0107] Diethylamino sulfur trifluoride (1.90 ml, 14.38 mmol) was addedto a methylene chloride (50 ml) solution of4-(S)-hydroxymethyl-N-[1-(R)-phenylethyl]-2-pyrrolidone (2.00 g, 9.12mmol) at −78° C., and the mixture was stirred overnight while graduallywarming to room temperature. The reaction solution was washed withsaturated sodium bicarbonate aqueous solution and saturated brine inthat order and then dried over anhydrous sodium sulfate. Afterevaporation of the solvent, the resulting residue was subjected to asilica gel chromatography to give 1.11 g (55%) of the title compoundfrom the 3% methanol-chloroform eluate in the form of a light yellowoil.

[0108] Method B:

[0109] Triethylamine (6.36 ml, 45.63 mmol) was added to a methylenechloride (100 ml) solution of4-(S)-hydroxymethyl-N-[1-(R)-phenylethyl]-2-pyrrolidone (5.00 g, 22.80mmol), methanesulfonyl chloride (2.65 ml, 34.24 mmol) was added dropwiseto the thus prepared solution which was cooled in an ice bath and thenthe resulting mixture was stirred for 30 minutes at the sametemperature. The reaction solution was washed with 10% citric acidaqueous solution and dried over sodium sulfate, and the solvent was thenevaporated. The thus obtained residue was dissolved in tetrahydrofuran(100 ml), mixed with 1N tetra-n-butylammonium fluoride-tetrahydrofuransolution (114 ml) and then heated under reflux for 1.5 hours. Thereaction solution was mixed with 10% citric acid aqueous solution,tetrahydrofuran was evaporated, the thus obtained residue was extractedwith chloroform (200 ml ×3) and then the resulting organic layers werecombined and dried over sodium sulfate. The solvent was evaporated andthe thus obtained residue was subjected to a silica gel chromatographyto give the title compound from the eluate of ethyl acetate:hexane=3:1,quantitatively in the form of a light yellow oil.

[0110]¹H-NMR (CDCl₃) δ: 1.52 (3H, d, J=7.33 Hz), 2.24-2.29 (1H, m),2.52-2.63 (2H, m), 3.10 (1H, t, J=9.76 Hz), 3.20 (1H, dd, J=5.37, 9.76Hz), 4.26-4.47 (2H, m), 5.50 (1H, q, J=7.32 Hz), 7.26-7.36 (5H, m).

REFERENCE EXAMPLE 2

[0111]4-(S)-Fluoromethyl-3-(R)-hydroxy-N-[1-(R)-phenylethyl]-2-pyrrolidone

[0112] In an atmosphere of nitrogen and at −78° C., 1.66 Nn-butyllithium-hexane solution (7.08 ml) was added dropwise to atetrahydrofuran (20 ml) solution of diisopropylamine (1.65 ml, 11.75mmol), and the mixture was stirred at 0° C. for 5 minutes. The reactionsolution was cooled to −78° C. and added dropwise to a tetrahydrofuran(20 ml) solution of4-(S)-fluoromethyl-N-[1-(R)-phenylethyl]-2-pyrrolidone (2.00 g, 9.04mmol) at −78° C. in an atmosphere of nitrogen. After 15 minutes ofstirring at the same temperature, degassing was effected under a reducedpressure, the atmosphere in the reaction container was replaced withoxygen gas and then the reaction mixture was stirred at the sametemperature in an atmosphere of oxygen. After completion of thereaction, the reaction solution was mixed with 5% sodium thiosulfateaqueous solution, tetrahydrofuran was evaporated, the thus obtainedresidue was extracted with ethyl acetate (150 ml×3) and then theresulting organic layers were combined and dried over sodium sulfate.The solvent was evaporated and the thus obtained residue was subjectedto a silica gel chromatography to give 1.57 g (73%) of the titlecompound from the eluate of 3% methanol-chloroform in the form of whitecrystals.

[0113]¹H-NMR (CDCl₃) δ: 1.52 (3H, d, J=7.32 Hz), 2.31-2.48 (1H, m),3.05-3.10 (1H, m), 3.16-3.21 (1H, m), 4.29 (1H, d, J=9.37 Hz), 4.53-4.67(2H, m), 5.48 (1H, q, J=7.33 Hz), 7.26-7.37 (5H, m).

REFERENCE EXAMPLE 3

[0114]3-(S)-Azido-4-(S)-fluoromethyl-N-[1-(R)-phenylethyl]-2-pyrrolidone

[0115] Triethylamine (3.07 ml, 22.02 mmol) was added to a methylenechloride (40 ml) solution of4-(S)-fluoromethyl-3-(R)-hydroxy-N-[1-(R)-phenylethyl]-2-pyrrolidone(2.61 g, 11.00 mmol), methanesulfonyl chloride (1.28 ml, 16.54 mmol) wasadded dropwise to the thus prepared solution at −10° C. and then theresulting mixture was stirred for 30 minutes at the same temperature.The reaction solution was washed with 10% citric acid aqueous solutionand dried over sodium sulfate and then the solvent was evaporated. Thethus obtained residue was dissolved in N,N-dimethylformamide (80 ml),mixed with sodium azide (2.86 g, 44.00 mmol) and then stirred overnightat 100° C. The reaction solution was mixed with water, extracted withethyl acetate (200 ml×3) and then the resulting organic layers werecombined and dried over sodium sulfate, subsequently evaporating thesolvent. The thus obtained residue was subjected to a silica gelchromatography to give 1.81 g (63%) of the title compound from theeluate of ethyl acetate:hexane=1:3 in the form of a light yellow oil.¹H-NMR (CDCl₃) δ: 1.56 (3H, d, J=7.32 Hz), 2.67-2.75 (1H, m), 3.02 (1H,dd, J=7.32, 10.25 Hz), 3.23 (1H, dd, J=4.39, 10.25 Hz), 4.27 (1H, d,J=8.30 Hz), 4.38 (1H, ddd, J=7.81, 9.28, 46.39 Hz), 4.59 (1H, ddd,J=5.86, 9.28, 46.37 Hz), 5.48 (1H, q, J=7.32 Hz), 7.26-7.37 (5H, m).

REFERENCE EXAMPLE 4

[0116]3-(S)-tert-Butoxycarbonylamino-4-(S)-fluoromethyl-N-[1-(R)-phenylethyl]-2-pyrrolidone

[0117] Di-tert-butyl dicarbonate (3.01 g, 13.79 mmol) and 10% palladiumon carbon catalyst (1.80 g) were added to an ethanol (100 ml) solutionof 3-(S)-azido-4-(S)-fluoromethyl-N-[1-(R)-phenylethyl]-2-pyrrolidone(1.81 g, 6.90 mmol), and the mixture was subjected to overnightcatalytic hydrogenation at room temperature. After removal of thecatalyst by filtration, the solvent of the resulting filtrate wasevaporated, and the thus obtained residue was subjected to a silica gelchromatography. From the eluate of ethyl acetate:hexane=1:2, 1.68 g(72%) of the title compound was obtained as white crystals.

[0118]¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.53 (3H, d, J=7.32 Hz), 2.85-2.93(1H, m), 3.06 (1H, dd, J=6.25, 10.74 Hz), 3.31 (1H, d, J=9.26 Hz),4.32-4.53 (3H, m), 5.08 (1H, brs), 5.49 (1H, q, J=6.83 Hz), 7.26-7.36(5H, m).

REFERENCE EXAMPLE 5

[0119]3-(S)-tert-Butoxycarbonylamino-4-(S)-fluoromethyl-N-[1-(R)-Phenylethyl]-2-pyrrolidine

[0120] While cooling in an ice bath, a 1 mol tetrahydrofuran solution(19.98 ml) of borane-tetrahydrofuran complex was added dropwise to atetrahydrofuran (60 ml) solution of3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethyl-N-[1-(R)-phenylethyl]-2-pyrrolidone(1.68 g, 4.99 mmol), and the resulting mixture was stirred overnight atroom temperature. The solvent was evaporated, and the thus obtainedresidue was mixed with an ethanol-water (4:1) mixed solvent (40 ml) andheated under reflux for 2 hours in the presence of triethylamine (8 ml).After spontaneous cooling, the solvent was evaporated. The thus obtainedresidue was mixed with chloroform and washed with saturated brine, theresulting organic layer was dried over sodium sulfate and then thesolvent was evaporated. The resulting residue was subjected to a silicagel chromatography to give 1.54 g (96%) of the title compound from theeluate of ethyl acetate:hexane=1:3 in the form of white crystals.

[0121]¹H-NMR (CDCl₃) δ: 1.35 (3H, d, J=6.84 Hz), 1.43 (9H, s), 2.38-2.78(5H, m), 3.24 (1H, q, J=6.34 Hz), 4.37-4.57 (3H, m), 4.84 (1H, d, J=8.30Hz), 7.25-7.35 (5H, m).

REFERENCE EXAMPLE 6

[0122] 3-(S)-tert-Butoxycarbonylamino-4-(S)-fluoromethylpyrrodine

[0123] 10% Palladium on carbon catalyst (500 mg) was added to an ethanol(50 ml) solution of3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethyl-N-[1-(R)-phenylethyl]-pyrrolidine(484 mg, 1.50 mmol), and the mixture was subjected to overnightcatalytic dehydrogenation at 50° C. After removing the catalyst byfiltration, the solvent in the resulting filtrate was evaporated to givecrude product of the title compound quantitatively.

[0124]¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 1.69 (1H, brs), 2.45-2.53 (1H, m),2.66 (1H, dd, J=5.37, 10.74 Hz), 2.90-2.95 (1H, m), 3.18 (2H, dd,J=7.81, 10.74 Hz), 4.18-4.27 (1H, m), 4.44-4.53 (1H, m), 4.56-4.65 (1H,m).

INVENTIVE EXAMPLE 1

[0125]7-[3-(S)-Amino-4-(S)-fluoromethyl-1-pyrrolidinyl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid

[0126] To a dimethyl sulfoxide (4 ml) solution of6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid BF₂ complex (360 mg, 1.0 mmol) were added3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethylpyrrolidine (218 mg,1.00 mmol) and triethylamine (400 μl), subsequently carrying out 1 dayof stirring at room temperature. Triethylamine was evaporated, theresulting residue was mixed with 10% citric acid aqueous solution andthen the thus precipitated material was collected by filtration andwashed with water. This was dissolved in 80% water-containing ethanol(50 ml), mixed with triethylamine (5 ml) and then heated overnight underreflux. The solvent was evaporated, and the thus obtained residue wasmixed with concentrated hydrochloric acid and stirred at roomtemperature for 15 minutes. The reaction solution was washed withchloroform and then, while cooling in an ice bath, alkalified with 50%sodium hydroxide aqueous solution. This was adjusted to pH 7.4 withconcentrated hydrochloric acid, and the aqueous layer was extracted withchloroform (300 ml×3). The organic layer was dried over sodium sulfate,the solvent was evaporated and then the resulting residue wasrecrystallized from 28% aqueous ammonia-ethanol to give 286 mg (70%) ofthe title compound in the form of light yellow crystals.

[0127]¹H-NMR (0.1N NaOD) δ: 1.41-1.62 (2H, m), 2.62-2.79 (1H, m),3.44-3.47 (1H, m), 3.57 (3H, s), 3.60-3.65 (1H, m), 3.70-3.73 (1H, m),3.77-3.88 (2H, m), 4.00-4.05 (1H, m), 4.55-5.08 (3H, m), 7.66 (1H, d,J=14.16 Hz), 8.42 (1H, d, J=2.44 Hz).

[0128] Elemental analysis data for C₁₉H₂₀F₃N₃O₄·0.25H₂O:

[0129] Calcd.: C, 54.87; H, 4.97; N, 10.10

[0130] Found : C, 54.78; H, 4.83; N, 10.00

[0131] Melting point: 232-238° C. (decomp.)

[0132] Specific rotation: [α]_(D)=−13.22° (c=0.174, 0.1 N sodiumhydroxide solution)

INVENTIVE EXAMPLE 2

[0133]7-[3-(S)-Amino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid

[0134] To a dimethyl sulfoxide (2 ml) solution of1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid EF₂ complex (345 mg, 1.00 mmol) were added3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethylpyrrolidine (327 mg,1.00 mmol) and triethylamine (400 μl), subsequently carrying out 1 dayof stirring at room temperature. Triethylamine was evaporated, theresulting residue was mixed with 10% citric acid aqueous solution andthen the thus precipitated material was collected by filtration andwashed with water. This was dissolved in 80% water-containing ethanol(50 ml), mixed with triethylamine (5 ml) and then heated overnight underreflux. The solvent was evaporated, and the thus obtained residue wasmixed with concentrated hydrochloric acid and stirred at roomtemperature for 15 minutes. The reaction solution was washed withchloroform and then, while cooling in an ice bath, alkalified with 50%sodium hydroxide aqueous solution. This was adjusted to pH 7.4 withconcentrated hydrochloric acid, and the aqueous layer was extracted withchloroform (300 ml×3). The organic layer was dried over sodium sulfate,the solvent was evaporated, and the resulting residue was isolated andpurified by a preparative TLC through its development with a lower layerof chloroform:methanol:water=7:3:1 and then recrystallized from 28%aqueous ammonia-ethanol to give 185 mg (47%) of the title compound inthe form of light yellow crystals.

[0135]¹H-NMR (0.1N NaOD) δ: 0.90-1.20 (4H, m), 2.73-2.78 (1H, m),3.41-3.44 (1H, m), 3.58 (3H, s), 3.64-3.73 (3H, m), 3.90-3.96 (1H, m),4.03-4.09 (1H, m), 4.66-4.82 (1H, m), 7.65 (1H, d, J=14.65 Hz), 8.49(1H, s).

[0136] Elemental analysis data for C₁₉H₂₁F₂N₃O₄·0.25H₂O:

[0137] Calcd.: C, 57.35; H, 5.45; N, 10.56

[0138] Found : C, 57.36; H, 5.46; N, 10.41

[0139] Melting point: 204-207° C. (decomp.)

[0140] Specific rotation: [α]_(D)=−92.00° (c=0.275, 0.1 N sodiumhydroxide solution)

REFERENCE EXAMPLE 7

[0141] 3-(S)-tert-Butoxycarbonylamino-4-(S)-fluoromethylpyrrolidine

[0142] 10% Palladium on carbon catalyst (640 mg) was added to an ethanol(15 ml) solution of 3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethyl-N-[1-(R)-phenylethyl]pyrrolidine (644 mg, 2.00 mmol), andthe mixture was subjected to 2 hours of catalytic hydrogenation at 50°C. After removal of the catalyst by filtration, the solvent in theresulting filtrate was evaporated, and the thus obtained residue wasmixed with 10% citric acid aqueous solution and washed withdichloromethane (15 ml×3) and diethyl ether (15 ml×1). The aqueous layerwas adjusted to pH 10 to 11 with IN sodium hydroxide aqueous solutionand then extracted with chloroform (50 ml×4). The organic layer wasdried over sodium sulfate, the solvent was evaporated and then theresulting residue was purified by recrystallizing it from achloroform-n-hexane mixed solvent to give 344 mg (79%) of the titlecompound in the form of white crystals.

[0143]¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.43-2.54 (1H, m), 2.67-2.70 (1H,m), 2.92-3.00 (1H, m), 3.18-3.25 (2H, m), 4.28 (1H, br.s.), 4.49 (1H,ddd, J=23.93, 9.28, 4.40 Hz), 4.61 (1H, ddd, J=23.93, 9.77, 4.40 Hz),4.89 (1H, br.s.).

[0144] IR (KBr disk) cm⁻¹: 3365, 3213, 2974, 2937, 2902, 2875, 1682,1525, 1458, 1444, 1392, 1369, 1336, 1300, 1288, 1281, 1248.

[0145] Elemental analysis data for C₁₀H₁₉FN₂O₂·0.25H₂O:

[0146] Calcd.: C, 53.92; H, 8.82; N, 12.57

[0147] Found : C, 54.25; H, 8.74; N, 12.74

[0148] Melting point: 78.0-79.3° C.

[0149] Specific rotation: [α]_(D)=+28.60° (c=1.035, chloroform)

INVENTIVE EXAMPLE 3

[0150]7-[3-(S)-Amino-4-(S)-fluoromethyl-1-pyrrolidinyl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[0151] To a dimethyl sulfoxide (4 ml) solution of6,7-difluoro-1-[2-(S)-fluoro-1-(R)cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid difluoroborane complex (360 mg, 1.00 mmol) were added3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethylpyrrolidine (218 mg,1.00 mmol) and triethylamine (400 μl), subsequently carrying out 1 dayof stirring at room temperature. The reaction solution was concentratedunder a reduced pressure, the thus concentrated solution was mixed with10% citric acid aqueous solution, and the thus precipitated material wascollected by filtration, washed with water, dissolved in a mixed solventof ethanol:water=4:1 (50 ml), mixed with triethylamine (5 ml) and thenheated overnight under reflux. The solvent was evaporated, and the thusobtained residue was mixed with concentrated hydrochloric acid andstirred at room temperature for 15 minutes. The reaction solution waswashed with chloroform and then, while cooling in an ice bath, theaqueous layer was alkalified with 50% sodium hydroxide aqueous solution.This was adjusted to pH 7.4 with concentrated hydrochloric acid and 1Nhydrochloric acid, and the aqueous layer was extracted with chloroform(300 ml×3). The organic layer was dried over sodium sulfate, the solventwas evaporated, and the resulting residue was recrystallized from 28%aqueous ammonia-ethanol to give 286 mg (70%) of the title compound inthe form of light yellow crystals.

[0152]¹H-NMR (0.1N NaOD) δ: 1.41-1.62 (2H, m), 2.62-2.79 (1H, m),3.44-3.47 (1H, m), 3.57 (3H, s), 3.60-3.65 (1H, m), 3.70-3.73 (1H, m),3.77-3.88 (2H, m), 4.00-4.05 (1H, m), 4.55-5.08 (3H, m), 7.66 (1H, d,J=14.16 Hz), 8.42 (1H, d, J=2.44 Hz).

[0153] Elemental analysis data for C₁₉H₂₀F₃N₃O₄·0.25H₂O:

[0154] Calcd.: C, 54.87; H, 4.97; N, 10.10

[0155] Found : C, 54.78; H, 4.83; N, 10.00

[0156] Melting point: 232-238° C. (decomp.)

[0157] Specific rotation: [α]_(D)=−13.22° (c=0.174, 0.1 N sodiumhydroxide solution)

INVENTIVE EXAMPLE 4

[0158] 7-3-(S)-Amino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid

[0159] To a dimethyl sulfoxide (2 ml) solution of1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid difluoroborane complex (345 mg, 1.00 mmol) were added3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethylpyrrolidine (327 mg,1.00 mmol) and triethylamine (400 μl), subsequently carrying out 1 dayof stirring at room temperature. The reaction solution was concentratedunder a reduced pressure, the thus concentrated solution was mixed with10% citric acid aqueous solution, and the thus precipitated material wascollected by filtration, washed with water, dissolved in a mixed solventof ethanol:water=4:1 (50 ml), mixed with triethylamine (5 ml) and thenheated overnight under reflux. The solvent was evaporated, and the thusobtained residue was mixed with concentrated hydrochloric acid andstirred at room temperature for 15 minutes. The thus treated residue waswashed with chloroform and then, while cooling in an ice bath, theaqueous layer was alkalified with 50% sodium hydroxide aqueous solution.This was adjusted to pH 7.4 with concentrated hydrochloric acid and 1Nhydrochloric acid, and the aqueous layer was extracted with chloroform(300 ml×3). The organic layer was dried over sodium sulfate, the solventwas evaporated, and the resulting residue was isolated and purified by apreparative TLC through its development with a lower layer ofchloroform:methanol:water=7:3:1 and then recrystallized from 28% aqueousammonia-ethanol to give 185 mg (47%) of the title compound in the formof light yellow crystals.

[0160]¹H-NMR (0.1N NaOD) δ: 0.90-1.20 (4H, m), 2.73-2.78 (1H, m),3.41-3.44 (1H, m), 3.58 (3H, s), 3.64-3.73 (3H, m), 3.90-3.96 (1H, m),4.03-4.09 (1H, m), 4.66-4.82 (1H, m), 7.65 (1H, d, J=14.65 Hz), 8.49(1H, s).

[0161] Elemental analysis data for C₁₉H₂₁F₂N₃O₄·0.25H₂O:

[0162] Calcd.: C, 57.35; H, 5.45; N, 10.56

[0163] Found : C, 57.36; H, 5.46; N, 10.41

[0164] Melting point: 204-207° C. (decomp.)

[0165] Specific rotation: [α]_(D)=−92.00° (c=0.275, 0.1 N sodiumhydroxide solution)

COMPARATIVE EXAMPLE 1

[0166]7-[3-(R)-Amino-4-(R)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid

[0167] To a dimethyl sulfoxide (2 ml) solution of1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid difluoroborane complex (507 mg, 1.48 mmol) were added3-(R)-tert-butoxycarbonylamino-4-(R)-fluoromethylpyrrolidine (419 mg,1.92 mmol) that has been synthesized in accordance with the proceduresdescribed in Reference Examples 1 to 6 using4-(R)-hydroxymethyl-N-[1-(R)-phenylethyl]-2-pyrrolidone which is adiastereomer of the starting material described in Reference Example 1,and triethylamine (454 μl), subsequently carrying out 38 hours ofstirring at room temperature. The reaction solution was concentratedunder a reduced pressure, the resulting residue was mixed with water (20ml) and then the thus precipitated crystals were collected by filtrationand washed with water. This was dissolved in a mixed solvent (30 ml) ofethanol:water=9:1, mixed with triethylamine (2 ml) and then heated underreflux for 4 hours. The solvent was evaporated, and the thus obtainedresidue was mixed with 10% citric acid aqueous solution (50 ml) andextracted with chloroform (100 ml×3). The organic layer was dried oversodium sulfate and the solvent was then evaporated. The thus obtainedresidue was dissolved in concentrated hydrochloric acid (10 ml) andwashed with dichloromethane (50 ml×3) and then, while cooling in an icebath, the aqueous layer was alkalified with 10 N sodium hydroxideaqueous solution. This aqueous layer was washed with dichloromethane (50ml×3), adjusted to pH 7.4 with concentrated hydrochloric acid and 1Nhydrochloric acid and then extracted with chloroform (100 ml×3). Theorganic layer was dried over sodium sulfate, the solvent was evaporated,and the resulting residue was purified by recrystallizing it from 28%aqueous ammonia-ethanol mixed solvent to give 472 mg (81%) of the titlecompound in the form of light yellow crystals.

[0168]¹H-NMR (0.1N NaOD) δ: 0.82-1.19 (4H, m), 2.65-2.75 (1H, m), 3.38(1H, d, J=10.75 Hz), 3.51 (3H, s), 3.59-3.70 (3H, m), 3.84-3.88 (1H, m),4.00-4.06 (1H, m), 4.64 -4.86 (2H, m), 7.61 (1H, d, J=14.65 Hz), 8.49(1H, s).

[0169] IR (KBr disk) cm⁻¹: 3359, 3086, 2952, 2881, 1724, 1620, 1510,1446, 1436, 1373, 1352, 1327, 1315, 1267, 1219.

[0170] Elemental analysis data for C₁₉H₂₁F₂N₃O₄:

[0171] Calcd.: C, 58.01; H, 5.38; N, 10.68

[0172] Found : C, 57.73; H, 5.40; N, 10.67

[0173] Melting point: 206.1-208.2° C.

[0174] Specific rotation: [α]_(D)=+95.21° (c=1.065, 0.1 N NaOH solution)

INVENTIVE EXAMPLE 5

[0175]7-[3-(S)-tert-Butoxycarbonylamino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid difluoroborane complex

[0176] To a dimethyl sulfoxide (2 ml) solution of1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid difluoroborane complex (343 mg, 1.00 mmol) were added3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethylpyrrolidine (284 mg,1.30 mmol) and triethylamine (307 μl), subsequently carrying out 21hours of stirring at room temperature. The reaction solution wasconcentrated under a reduced pressure, the thus concentrated solutionwas mixed with water (50 ml) and then the thus precipitated crystalswere washed with water and diethyl ether. These crystals were purifiedby recrystallizing them from ethanol to give 285 mg (53%) of the titlecompound in the form of light yellow crystals.

[0177]¹H-NMR (CDCl₃) δ: 1.14-1.21 (2H, m), 1.33-1.36 (2H, m), 1.47 (9H,s), 2.78-2.84 (1H, m), 3.64 (4H, s), 3.87-3.90 (1H, m), 4.02-4.07 (1H,m), 4.29-4.31 (1H, m), 4.55 (1H, br.s), 4.61-4.83 (2H, m), 5.00 (1H,br.s), 7.84 (1H, d, J=13.67 Hz), 8.97 (1H, s).

[0178] IR (KBr disk) cm⁻¹: 3423, 2981, 1716, 1631, 1568, 1524, 1502,1443, 1410, 1394, 1367, 1338, 1286, 1254.

[0179] Elemental analysis data for C₂₄H₂₈BF₄N₃O₆·0.75H₂O:

[0180] Calcd.: C, 51.96; H, 5.36; N, 7.57

[0181] Found : C, 52.07; H, 5.27; N, 7.57

[0182] Melting point: 154.3-155.2° C. (decomp.)

[0183] Specific rotation: [α]_(D)=−1.03° (c=0.968, chloroform)

INVENTIVE EXAMPLE 6

[0184]7-[3-(S)-tert-Butoxycarbonylamino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid

[0185]7-[3-(S)-tert-Butoxycarbonylamino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid difluoroborane complex (244 mg, 440 μmol) was dissolved in a mixedsolvent (20 ml) of ethanol:water=4:1 and mixed with triethylamine (2ml), and the mixture was heated under reflux for 4 hours. The solventwas evaporated, and the resulting residue was mixed with 10% citric acidaqueous solution (50 ml) and extracted with chloroform (100 ml×3). Theorganic layer was dried over sodium sulfate and the solvent wasevaporated to give 256 mg of crude product of the title compound whichwas then purified by its recrystallization from a chloroform-n-hexanemixed solvent to give 194 mg (87%) of the title compound in the form oflight yellow crystals.

[0186]¹H-NMR (0.1N NaOD) δ: 0.68-1.05 (4H, m), 1.30 (9H, s), 2.70-2.80(1H, m), 3.34 (1H, d, J=10.26 Hz), 3.44 (3H, s), 3.52 (1H, t, J=8.30Hz), 3.62 (1H, t, J=8.30 Hz), 3.83-3.85 (1H, m), 3.90-3.95 (1H, m), 4.27(1H, br.s), 4.43-4.62 (2H, m), 7.51 (1H, d, J=14.16 Hz), 8.34 (1H, s).

[0187] IR (KBr disk) cm⁻¹: 3359, 3086, 2976, 2935, 2881, 1716, 1624,1512, 1450, 1392, 1369, 1313, 1273, 1248.

[0188] Elemental analysis data for C₂₄H₂₉F₂N₃O₆·0.5H₂O:

[0189] Calcd.: C, 57.36; H, 6.02; N, 8.36

[0190] Found : C, 57.40; H, 5.97; N, 8.21

[0191] Melting point: 111.0-113.7° C.

[0192] Specific rotation: [α]_(D)=−21.17° (c=0.992, chloroform)

INVENTIVE EXAMPLE 7

[0193]7-[3-(S)-Amino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid

[0194] Concentrated hydrochloric acid (2 ml) was added to7-[3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-B-methoxy-4-oxoquinoline-3-carboxylicacid (140 mg, 0.28 mmol) which was cooled in an ice bath, and themixture was stirred for 30 minutes at the same temperature. The reactionsolution was diluted with water (50 ml) and washed with chloroform (50ml×3) and then, while cooling in an ice bath, the aqueous layer wasalkalified with 50% sodium hydroxide aqueous solution. The aqueous layerwas washed with dichloromethane (50 ml×3), adjusted to pH 7.4 withconcentrated hydrochloric acid and 1N hydrochloric acid and thenextracted with chloroform (100 ml×3). The organic layer was dried oversodium sulfate, the solvent was evaporated, and the thus obtainedresidue was purified by its recrystallization from a 28% aqueousammonia-ethanol mixed solvent to give 94 mg (85%) of the title compoundin the form of light yellow crystals.

[0195]¹H-NMR (0.1N NaOD) δ: 0.79-1.12 (4H, m), 2.65-2.71 (1H, m), 3.35(1H, d, J=10.74 Hz), 3.49 (3H, s), 3.60-3.67 (3H, m), 3.83-3.88 (1H, m),3.98-4.02 (1H, m), 4.58-4.79 (2H, m), 7.58 (1H, d, J=14.64 Hz), 8.42(1H, s).

[0196] IR (KBr disk) cm⁻¹: 3452, 3072, 2952, 2881, 1726, 1622, 1512,1446, 1439, 1369, 1352, 1315, 1267.

[0197] Melting point: 203.2-205.1° C. (decomp.)

[0198] Elemental analysis data for C₁₉H₂₁F₂N₃O₄·0.25H₂O:

[0199] Calcd.: C, 57.35; H, 5.37; N, 10.56

[0200] Found : C, 57.56; H, 5.37; N, 10.59

[0201] Specific rotation: [α]_(D)=−90.45° (c=0.995, 0.1 N NaOH solution)

INVENTIVE EXAMPLE 8

[0202]7-[3-(S)-tert-Butoxycarbonylamino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid diacetoxyborane complex

[0203] To an acetonitrile (3 ml) solution of1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid diacetoxyborane complex (423 mg, 1.00 mmol) were added3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethylpyrrolidine (327 mg,1.50 mmol) and triethylamine (280 μl), subsequently carrying out 15hours of stirring at room temperature. The reaction solution wasconcentrated under a reduced pressure, and the thus concentratedsolution was mixed with chloroform (50 ml) and washed with 10% citricacid aqueous solution and saturated brine in that order. The organiclayer was dried over sodium sulfate, the solvent was evaporated, and thethus obtained residue was subjected to a silica gel columnchromatography. The crystals obtained from the eluate ofchloroform:methanol=97:3 were purified by their recrystallization from achloroform-n-hexane mixed solvent to give 599 mg (93%) of the titlecompound in the form of yellow crystals.

[0204]¹H-NMR (CDCl₃) δ: 1.11-1.18 (2H, m), 1.26-1.31 (2H, m), 1.47 (9H,s), 2.05 (6H, s), 2.75-2.83 (1H, m), 3.57 (3H, s), 3.57-3.64 (1H, m),3.78-3.83 (1H, m), 3.94-4.06 (2H, m), 4.15-4.20 (1H, m), 4.53-4.88 (4H,m), 7.89 (1H, d, J=13.18 Hz), 9.06 (1H, s).

[0205] IR (KBr disk) cm⁻¹: 3318, 2973, 1716, 1631, 1571, 1529, 1446,1369, 1338, 1274, 1249.

[0206] Elemental analysis data for C₂₈H₃₂BF₂N₃O₁₀·0.5H₂O:

[0207] Calcd.: C, 52.58; H, 5.44; N, 6.57

[0208] Found : C, 52.51; H, 5.75; N, 6.28

[0209] Melting point: 142.4-144.2° C. (decomp.)

[0210] Specific rotation: [α]_(D)=−8.04° (c=1.032, chloroform)

INVENTIVE EXAMPLE 9

[0211]7-[3-(S)-tert-Butoxycarbonylamino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid

[0212]7-[3-(S)-tert-Butoxycarbonylamino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid diacetoxyborane complex (435 mg, 0.70 mmol) was suspended in amixed solution (10 ml) of ethanol:water=4:1 and mixed with triethylamine(2 ml), and the suspension was heated under reflux for 10 hours. Thereaction solution was concentrated under a reduced pressure, and theresulting residue was mixed with chloroform (50 ml) and washed with 10%citric acid aqueous solution and water. The organic layer was dried oversodium sulfate, the solvent was evaporated, and the resulting residuewas purified by its recrystallization from an ethanol-n-hexane mixedsolvent to give 272 mg (79%) of the title compound in the form of lightyellow crystals.

[0213] Its data of various instrumental analyses such as ¹H-NMR and thelike coincided with the data described in Inventive Example 6.

REFERENCE EXAMPLE 8

[0214] 3-(S)-Amino-4-(S)-fluoromethylpyrrolidine dihydrochloride

[0215] Concentrated hydrochloric acid (1 ml) was added to3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethylpyrrolidine (441 mg,2.02 mmol) which was cooled in an ice bath, and the mixture was stirredfor 10 minutes. The reaction solution was mixed with water (5 ml) andwashed with dichloromethane (5 ml×3) and diethyl ether (5 ml×1). Theaqueous layer was concentrated under a reduced pressure, and theresulting residue was purified by its recrystallization from methanol togive 288 mg (75%) of the title compound in the form of white crystals.

[0216]¹H-NMR (D₂O) δ: 3.07 (1H, br.d, J=33.69 Hz), 3.51-3.61 (2H, m),3.74 (1H, dd, J=12.69, 7.81 Hz), 3.90 (1H, dd, J=13.18, 7.81 Hz), 4.33(1H, dd, J=13.18, 7.32 Hz), 4.75-4.99 (2H, m).

[0217] IR (KBr disk) cm⁻¹: 2910, 2594, 2445, 1610, 1581, 1558, 1504,1450, 1411, 1394, 1375, 1358, 1329, 1308, 1292, 1267, 1242, 1209.

[0218] Elemental analysis data for C₅H₁₁FN₂·2HCl:

[0219] Calcd.: C, 31.43; H, 6.83; N, 14.66

[0220] Found : C, 31.29; H, 6.87; N, 14.58

[0221] Melting point: 198.1-199.0° C.

[0222] Specific rotation: [α]_(D)=−2.81° (c=1.033, H₂O)

INVENTIVE EXAMPLE 10

[0223]7-[3-(S)-Amino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid difluoroborane complex

[0224] To a dimethyl sulfoxide (2 ml) solution of1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid difluoroborane complex (343 mg, 1.00 mmol) were added3-(S)-amino-4-(S)-fluoromethylpyrrolidine dihydrochloride (268 mg, 1.40mmol) and triethylamine (585 μl), subsequently carrying out 15 hours ofstirring at room temperature. The reaction solution was concentratedunder a reduced pressure, the thus concentrated solution was mixed withwater (100 ml), washed with chloroform (50 ml×3) and then adjusted to pH6.9 by adding saturated sodium bicarbonate aqueous solution, and theaqueous layer was extracted with chloroform (100 ml×4). The organiclayer was dried over sodium sulfate, the solvent was evaporated, and theresulting residue was purified by its recrystallization from ethanol togive 412 mg (92%) of the title compound in the form of light yellowcrystals.

[0225]¹H-NMR (CDCl₃) δ: 1.03-1.43 (4H, m), 2.65-2.71 (1H, m), 3.49-3.53(1H, m), 3.64 (3H, s), 3.72-3.76 (1H, m), 3.77-3.79 (1H, m), 4.05-4.10(1H, m), 4.26-4.30 (1H, m), 4.76 (2H, br.d, J=46.64 Hz), 7.88 (1H, d,J=13.68 Hz), 8.97 (1H, s).

[0226] IR (KBr disk) cm⁻¹: 3064, 2944, 2889, 1722, 1633, 1566, 1520,1504, 1444, 1402, 1363, 1329, 1290, 1250, 1220.

[0227] Elemental analysis data for C₁₉H₂₀BF₄N₃O₄·−0.25H₂O:

[0228] Calcd.: C, 51.20; H, 4.64; N, 9.43

[0229] Found : C, 51.00; H, 4.54; N, 9.35

[0230] Melting point: 214.1-214.7° C. (decomp.)

[0231] Specific rotation: [α]_(D)=−125.800 (c=0.996,N,N-dimethylformamide)

INVENTIVE EXAMPLE 11

[0232]7-[3-(S)-Amino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid

[0233]7-[3-(S)-Amino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid difluoroborane complex (348 mg, 781 μmol) was dissolved in a mixedsolution (20 ml) of ethanol:water=4:1 and mixed with triethylamine (2ml), and the mixture was heated under reflux for 4 hours. The solventwas evaporated, and the resulting residue was dissolved by addingconcentrated hydrochloric acid and 1N hydrochloric acid, washed withchloroform (50 ml×3) and then, while cooling in an ice bath, alkalifiedwith 50% sodium hydroxide aqueous solution. The aqueous layer was washedwith dichloromethane (50 ml×3), adjusted to pH 7.4 with concentratedhydrochloric acid and 1N hydrochloric acid and then extracted withchloroform (100 ml×3). The organic layer was dried over sodium sulfate,the solvent was evaporated, and then the resulting residue was purifiedby its recrystallization from a 28% aqueous ammonia-ethanol mixedsolvent to give 205 mg (67%) of the title compound in the form of lightyellow crystals.

[0234] Its data of various instrumental analyses such as ¹H-NMR and thelike coincided with the data described in Inventive Example 7.

INVENTIVE EXAMPLE 12

[0235] 7-[3-(S)-Amino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid diacetoxyborane complex

[0236] To an acetonitrile (3 ml) solution of1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid diacetoxyborane complex (423 mg, 1.00 mmol) were added3-(S)-amino-4-(S)-fluoromethylpyrrolidine dihydrochloride (287 mg, 1.50mmol) and triethylamine (700 μl), subsequently carrying out 15 hours ofstirring at room temperature. The reaction solution was concentratedunder a reduced pressure, and the thus obtained residue was mixed withchloroform (50 ml), washed with water and then dried over sodiumsulfate. The solvent was evaporated, the resulting residue was subjectedto a silica gel column chromatography and then the crystals thusobtained from the eluate of chloroform:methanol=10:1 were washed withether to give 459 mg (88%) of the title compound in the form of lightyellow crystals.

[0237]¹H-NMR (CDCl₃) δ: 1.03-1.41 (4H, m), 2.05 (6H, s), 2.64-2.70 (1H,m), 3.43-3.47 (1H, m), 3.57 (3H, s), 3.68-3.72 (1H, m), 3.83-3.89 (2H,m), 4.02-4.07 (1H, m), 4.17-4.20 (1H, m), 4.67-4.70 (1H, m), 4.79-4.82(1H, m), 7.87 (1H, d, J=13.19 Hz), 9.04 (1H, s).

[0238] IR (KBr disk) cm⁻¹: 3378, 2931, 2884, 1716, 1627, 1573, 1527,1446, 1373, 1338, 1280, 1243, 1218.

[0239] Elemental analysis data for C₂₃H₂₆BF₂N₃O₈·−0.5H₂O:

[0240] Calcd.: C, 52.09; H, 5.13; N, 7.92

[0241] Found : C, 52.11; H, 5.36; N, 7.80

[0242] Melting point: 182.4-185.6° C. (decomp.)

[0243] Specific rotation: [α]_(D)=−80.02° (c=1.001, chloroform)

INVENTIVE EXAMPLE 13

[0244]7-[3-(S)-Amino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid

[0245]7-[3-(S)-Amino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid diacetoxyborane complex (365 mg, 0.70 mmol) was suspended in amixed solution (10 ml) of ethanol:water=4:1 and mixed with triethylamine(2 ml), and the mixture was heated under reflux for 14 hours. Thereaction solution was concentrated under a reduced pressure, and thethus obtained residue was dissolved by adding concentrated hydrochloricacid and 1 N hydrochloric acid and washed with chloroform (50 ml×3) andthen, while cooling in an ice bath, the aqueous layer was alkalifiedwith 50% sodium hydroxide aqueous solution. The aqueous layer was washedwith dichloromethane (50 ml×3), adjusted to pH 7.4 with concentratedhydrochloric acid and 1N hydrochloric acid and then extracted withchloroform (100 ml×3). The organic layer was dried over sodium sulfate,the solvent was evaporated, and then the resulting residue was purifiedby its recrystallization from a 28% aqueous ammonia-ethanol mixedsolvent to give 218 mg (81%) of the title compound in the form of lightyellow crystals.

[0246] Its data of various instrumental analyses such as ¹H-NMR and thelike coincided with the data described in Inventive Example 7. TABLE 1Antibacterial activity (minimum inhibitory concentration, μg/ml)Compounds Strains Ex. 1 Ex. 2 Comp. Ex. 1 E. coli, NIHJ ≦0.003 ≦0.003≦0.003 S. flexneli, 2A 5503 0.006 0.006 0.013 Pr. vulgaris, 08601 0.0130.013 0.013 Pr. mirabilis, IFO- 3849 0.025 0.05 0.10 Ser. marcescens,10100 0.05 0.05 0.10 Ps. aeruginosa, 32104 0.20 0.20 0.20 Ps.aeruginosa, 32121 0.05 0.10 0.10 X. maltophilia, IID 1275 0.20 0.10 0.20S. aureus, 209P 0.013 0.013 0.025 S. epidermidis, 56500 0.05 0.05 0.10Str. pyogenes, G-36 0.10 0.10 0.20 Str. faecalis, ATCC- 0.10 0.10 0.2019433 S. aureus, 870307 0.20 0.39 0.78

INDUSTRIAL APPLICABILITY

[0247] Thus, as has been described in the foregoing, the compound of thepresent invention is possessed of excellent antibacterial activity andsafety, so that it is useful as medicaments.

1. A compound represented by the following formula (I), its salts orhydrates thereof:

wherein R¹ represents a hydrogen atom or an alkyl group having 1 to 6carbon atoms, wherein said alkyl group may have one or more substituentselected from the group consisting of a hydroxyl group, a halogen atom,an alkylthio group having 1 to 6 carbon atoms and an alkoxyl grouphaving 1 to 6 carbon atoms, R² represents a halogenomethoxyl group or analkoxyl group having 1 to 6 carbon atoms, R³ represents an alkyl grouphaving 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms,a halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl grouphaving 3 to 6 carbon atoms which may have a substituent, a heteroarylgroup which may have a substituent, an alkoxyl group having 1 to 6carbon atoms or an alkylamino group having 1 to 6 carbon atoms, and R⁴represents a hydrogen atom, a phenyl group, an acetoxymethyl group, apivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, adimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group,an alkyl group having 1 to 6 carbon atoms, an alkoxylmethyl group having2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene grouphaving 1 to 6 carbon atoms and a phenyl group.
 2. The compound, itssalts or hydrates thereof according to claim 1, wherein R¹ in theformula (I) is a hydrogen atom.
 3. The compound, its salts or hydratesthereof according to claim 1 or 2, wherein R² in the formula (I) is amethoxyl group.
 4. The compound, its salts or hydrates thereof accordingto claim 1, 2 or 3, wherein R³ in the formula (I) is a cyclopropylgroup.
 5. The compound, its salts or hydrates thereof according to claim1, 2 or 3, wherein R³ in the formula (I) is a halogenocyclopropyl group.6. The compound, its salts or hydrates thereof according to claim 1, 2or 3, wherein R³ in the formula (I) is a 1,2-cis-halogenocyclopropylgroup.
 7. The compound, its salts or hydrates thereof according to claim1, 2, 3, 5 or 6, wherein R³ in the formula (I) is a stereochemicallypure substituent.
 8. The compound, its salts or hydrates thereofaccording to claim 1, 2, 3, 5, 6 or 7, wherein the R³ in the formula (I)is a (1R,2S)-2-halogenocyclopropyl group.
 9. The compound, its salts orhydrates thereof according to claim 1, 2, 3, 5, 6, 7 or 8, wherein R³ inthe formula (I) is a (1R,2S)-2-fluorocyclopropyl group.
 10. Thecompound, its salts or hydrates thereof according to any one of theclaims 1 to 9, wherein the compound of formula (I) is a stereochemicallypure compound. 11.7-[3-(S)-Amino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof. 12.7-[3-(S)-Amino-4-(S)-fluoromethyl-1-pyrrolidinyl]-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid, its salts or hydrates thereof.
 13. A medicament which comprises acompound described in any one of claims 1 to 12, a hydrate thereof, asalt of the compound or a hydrate of the salt as an active ingredient.14. An antibacterial agent which comprises a compound described in anyone of claims 1 to 12, a hydrate thereof, a salt of the compound or ahydrate of the salt as an active ingredient.
 15. A compound representedby the following formula (II), its salts or hydrates thereof:

wherein R¹¹ and R¹², each independently represents a hydrogen atom, analkyl group having 1 to 6 carbon atoms or a protective group of theamino group, wherein said alkyl group may have one or moresubstituent(s) selected from the group consisting of a hydroxyl group, ahalogen atom, an alkylthio group having 1 to 6 carbon atoms and analkoxyl group having 1 to 6 carbon atoms, and Q′ represents a protectivegroup of the amino group or a hydrogen atom.
 16. The compound, its saltsor hydrates thereof according to claim 15, wherein the protective groupof the amino group is a protective group selected from the groupconsisting of (substituted) alkoxycarbonyl groups, (substituted)aralkyloxycarbonyl groups, (substituted) acyl groups, (substituted)alkyl groups, (substituted) aralkyl groups and silyl groups.
 17. Thecompound, its salts or hydrates thereof according to claim 15 or 16,wherein the protective group of the amino group is a protective groupselected from the group consisting of a tert-butoxycarbonyl group, a2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, apara-methoxybenzyloxycarbonyl group, a para-nitrobenzyloxycarbonylgroup, an acetyl group, a methoxyacetyl group, a trifluoroacetyl group,a chloroacetyl group, a pivaloyl group, a formyl group, a benzoyl group,a tert-butyl group, a benzyl group, a para-nitrobenzyl group, apara-methoxybenzyl group, a (R)-1-phenylethyl group, a (S)-1-phenylethylgroup, a triphenylmethyl group, a methoxymethyl group, atert-butoxymethyl group, a tetrahydropyranyl group, a2,2,2-trichloroethoxymethyl group, a trimethylsilyl group, anisopropyldimethylsilyl group, a tert-butyldimethylsilyl group, atribenzylsilyl group and a tert-butyldiphenylsilyl group.
 18. Thecompound, its salts or hydrates thereof according to claim 15, 16 or 17,wherein one of R¹¹ and R¹² and Q′ are protective groups of the aminogroup, which are different from each other. 19.3-(S)-tert-Butoxycarbonylamino-4-(S)-fluoromethyl-1-(R)-phenylethylpyrrolidine,its salts or hydrates thereof. 20.3-(S)-tert-Butoxycarbonylamino-4-(S)-fluoromethylpyrrolidine, its saltsor hydrates thereof.
 21. The compound, its salts or hydrates thereofaccording to claim 15, 16 or 17, wherein one of R¹¹ and R¹² and Q′ areprotective groups of the amino group, which are severed under differentreaction conditions.